This invention is in the area of phenylindoles that are useful for the treatment of HIV infection, and, in particular, phenylindoles that exhibit significant activity against resistant strains of HIV.
In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). Numerous compounds have since been synthesized to combat the virus, designed to inhibit progression beyond various stages of the virus""s lifecycle. A focal point in AIDS research efforts has been the development of inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT), an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA (Greene, W. C., New England Journal of Medicine, 1991, 324, 308-317; Mitsuya, H. et al., Science, 1990, 249, 1533-1544; De Clercq, E., J. Acquired Immune Defic. Syndr. Res. Human. Retrovirus, 1992, 8, 119-134). Promising inhibitors include nonnucleoside inhibitors (NNI), which bind to a specific allosteric site of HIV-1 RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al., Science, 1992, 256, 1783-1790).
Several classes of compounds have been identified as NNI of HIV-1 RT. Examples include the following:
(a) 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPT; Tanaka, H. et al., J. Med. Chem., 1991, 34, 349-357; Pontikis, R. et al., J. Med. Chem., 1997, 40, 1845-1854; Danel, K., et al., J. Med. Chem., 1996, 39, 2427-2431; Baba, M., et al., Antiviral Res, 1992, 17, 245-264);
(b) bis(heteroaryl)piperazines (BHAP; Romero, D. L. et al., J. Med. Chem., 1993, 36, 1505-1508);
(c) dihydroalkoxybenzyloxopyrimidine (DABO; Danel, K. et al., Acta Chemica Scandinavica, 1997, 51, 426-430; Mai, A. et al., J. Med. Chem., 1997, 40, 1447-1454);
(d) 2xe2x80x2-5xe2x80x2-bis-O-(tertbutyldimethylsilyl)-3xe2x80x2-spiro-5xe2x80x3-(4xe2x80x3-amino-1xe2x80x3, 2xe2x80x3-oxathiole-2xe2x80x3, 2xe2x80x3-dioxide) pyrimidines (TSAO; Balzarini, J. et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 4392-4396);
(e) phenethylthiazolylthiourea (PETT) derivatives (Bell, F. W. et al., J. Med. Chem., 1995, 38, 4929-4936; Cantrell, A. S. et al., J. Med. Chem., 1996, 39, 4261-4274);
(f) tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2 (1H)-one and -thione (TIBO) derivatives (Pauwels, R. et al. Nature, 1990, 343, 470-474);
(g) alpha-anilinophenylacetamide (alpha-APA) derivatives (Pauwels, R. et al. Proceedings of the National Academy of Sciences USA, 1993, 90, 1711-1715); and
(h) indole derivatives (Williams et al., U.S. Pat. No. 5,527,819 (Jun. 18, 1996); and its counterpart PCT application PCT/US94/01694, published as WO 94/19321 on Sep. 1, 1994).
The indole derivatives identified by Williams et al., assigned to Merck and Co., in U.S. Pat. No. 5,527,819 received particular interest because of their ability to potently inhibit HIV reverse transcriptase. A number of these compounds displayed EC90s against HIV reverse transcriptase at concentrations as low as 2 micromolar. However, this work was not pursued, perhaps because HIV virus that had been exposed to other drugs was shown to be cross resistant to these indoles (Williams et al., Journal of Medicinal Chemistry, 1993, 36(9), 1291-94).
The class of compounds disclosed in the ""819 patent encompasses a large class of compounds represented generally by the following broad structural formula: 
in which the variables X, Y, Z, R and R6 were broadly defined to encompass a plethora of compoundS. The patent presented examples for nearly one hundred of the compounds encompassed by the structure, and included several examples in which Z was xe2x80x94C(O)NH2, Y was SO2 and R was phenyl or substituted phenyl.
U.S. Pat. No. 5,124,327, issued Jun. 23, 1992 to Greenlee et al. and assigned to Merck disclosed a class of compounds of the general formula above, in which X is H, R6 is H, Y is S, and R is phenyl. The patent disclosed that the compounds act as reverse transcriptase inhibitors.
Indoles have been used for the treatment of a variety of diseases other than HIV. For example, Farina et al., in U.S. Pat. No. 5,981,525 (Nov. 9, 1999), disclose a complex array of indoles that are useful for the treatment of osteoporosis, because they reduce bone resorption by inhibiting osteoclast H+-ATPase.
U.S. Pat. No. 6,025,390, granted Feb. 15, 2000 to Farina et al., discloses another complex array of indole derivatives, referred to as heteroaromatic pentadienoic acid derivatives, and again suggest their use for the treatment of osteoporosis.
U.S. Pat. No. 5,489,685, granted Feb. 6, 1996, Houpis et al. discloses a similar set of compounds in the furo(2,3-B) pyridine carboxylic acid ester class, and specifically suggest their use for the treatment of HIV.
U.S. Pat. No. 5,945,440 to Kleinschroth et al. discloses a class of indolocarbazole amides, and proposes their use for a variety of diseases including cancer, viral diseases (including HIV), heart and blood vessel diseases, bronchopulmonary diseases, degenerative diseases of the central nervous system, inflammatory disorders, and other diseases.
Gunasekera et al., in U.S. Pat. No. 4,866,084 (Sep. 12, 1989), disclose a class of bisindole alkaloid compounds, and state that the compounds are useful as antiviral and antitumor agents. The patent also describes the compounds"" activity against HSV (herpes simplex virus).
Matsunaga et al., in U.S. Pat. No. 5,852,011 (Dec. 22, 1998), disclose a class of indole derivates substituted by a heteroaryl function and an amide function. The compounds are said to possess antitumor, antiviral, and antimicrobial properties.
Dykstra et al., in U.S. Pat. No. 5,935,982 disclose a class of bis-indoles and specifically propose their use for treating retroviral infections, and especially infection by HIV.
Domagala et al., in U.S. Pat. No. 5,929,114 (Jul. 27, 1999) disclose a class of arylthio and bithiobisarylamide compounds that reportedly have antibacterial and antiviral activity. The invention is said to encompass indole derivatives as well.
Pevear et al., in U.S. Pat. No. 5,830,894 (Nov. 3, 1998) disclose a class of triazinoindole derivatives that reportedly have pestivirus activity, most notably BVDV activity.
It is known that over a period of time, antiviral agents that are active against HIV induce mutations in the virus that reduce the efficacy of the drug. This was apparently the problem exhibited by the Merck indoles in U.S. Pat. No. 5,527,819 (Williams et al., Journal of Medicinal Chemistry, 1993, 36(9), 1291-94). Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease, or DNA integrase. It has been demonstrated that the efficacy of a drug against HIV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution, or other parameters of a drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy since combination therapy induces multiple simultaneous pressures on the virus. However, one cannot predict which mutations will be induced in the HIV-1 genome by a given drug, whether the mutations are permanent or transient, or how an infected cell with a mutated HIV-1 sequence will respond to therapy with other agents in combination or alternation. These factors are exacerbated by the fact that there is a paucity of data on the kinetics of drug resistance in long-term cell cultures treated with modem antiretroviral agents.
Therefore, there is a need to improve the duration of antiviral efficacy produced by antiretroviral drugs, and to provide antiviral drugs that are effective against strains of the virus that have developed cross resistance through mutational adaptation. Further, although many of the non-nucleotide reverse transcriptase inhibitors (NNRTI) in the prior art exhibit favorable pharmacokinetic and biodistribution profiles, there remains a need to improve upon these parameters.
It is an object of the present invention to provide new compounds for the treatment of patients infected with HIV. There is a special need to provide new compositions and methods for the treatment of patients infected with HIV that exhibit significant activity against drug-resistant forms of the virus.
A novel class of phenylindoles has been discovered that display significant antiviral activity against HIV, and in particular, strains of the HIV that have developed cross resistance to other anti-HIV drugs. It has surprisingly been discovered that HIV activity can be enhanced, and in certain cases cross resistance can be substantially overcome, by incorporating into the molecule at least two moieties other than hydrogen on either the phenyl ring or the benzyl ring of the indole function, or on both rings. The substituents are preferably contained at the 3xe2x80x3 and 5xe2x80x3 positions if located on phenyl ring, and at the 4xe2x80x2 and 5xe2x80x2; 5xe2x80x2 and 6xe2x80x2 or the 5xe2x80x2 and 7xe2x80x2 positions if located on the benzyl ring of the indole function. Methyl is a preferred group for substitution on the phenyl ring. Preferred substituents for the benzyl ring of the indole function are small moieties, and include substituents such as chlorine, fluorine, bromine, CF3, vinyl bromide and NO2.
In one embodiment of the present invention, the compound can be represented generally by the following chemical formula: 
or its pharmaceutically acceptable salt or prodrug, wherein
(a) R1 is hydrogen; acyl; xe2x80x94C(xe2x95x90O)H; xe2x80x94C(xe2x95x90W)H; xe2x80x94C(xe2x95x90O)R2; xe2x80x94C(xe2x95x90W)R2; xe2x80x94C(xe2x95x90O)OH; xe2x80x94C(xe2x95x90W)OH; xe2x80x94C(xe2x95x90O)OR2; xe2x80x94C(xe2x95x90W)OR2; xe2x80x94C(xe2x95x90O)SH; xe2x80x94C(xe2x95x90W)SH; xe2x80x94C(xe2x95x90O)SR2; xe2x80x94C(xe2x95x90W)SR2; xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90W)NH2; xe2x80x94C(xe2x95x90O)NHR2; xe2x80x94C(xe2x95x90W)NHR2; xe2x80x94C(xe2x95x90O)NR2RW; xe2x80x94C(xe2x95x90W)NR2R3; xe2x80x94C(xe2x95x90W)NHxe2x80x94(CH2)p-(amino acid) or xe2x80x94(CH2)p-(amino acid);
(b) R4xe2x80x2, R5xe2x80x2, R6xe2x80x2, R7xe2x80x2, R2xe2x80x3, R3xe2x80x3, R4xe2x80x3, R5xe2x80x3 and R6xe2x80x3 are each independently H; halo (F, Cl, Br or I); xe2x80x94NO2; xe2x80x94CN; xe2x80x94OH; xe2x80x94OR2; xe2x80x94SH; xe2x80x94SR2; xe2x80x94NH2; xe2x80x94NHR2; xe2x80x94NR2R3; xe2x80x94NHSO2xe2x80x94C1-3alkyl; xe2x80x94NR2SO2xe2x80x94C1-3alkyl; xe2x80x94NHCOxe2x80x94C1-3alkyl; xe2x80x94NR2COxe2x80x94C1-3alkyl; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and in particular CH3, CF3, vinyl bromide, xe2x80x94CR2R2xe2x80x94S(O)nxe2x80x94R3, xe2x80x94CR2R2NH2, xe2x80x94CR2R2NHR2, xe2x80x94CR2R2NR2R3 and xe2x80x94CR2R2xe2x80x94C(xe2x95x90O)R2); alkacyl; optionally substituted or unsubstituted acyl; xe2x80x94C(xe2x95x90O)H; xe2x80x94C(xe2x95x90W)H; xe2x80x94C(xe2x95x90O)R2; xe2x80x94C(xe2x95x90W)R2; xe2x80x94C(xe2x95x90O)OH; xe2x80x94C(xe2x95x90W)OH; xe2x80x94C(xe2x95x90O)OR2; xe2x80x94C(xe2x95x90W)OR2; xe2x80x94C(xe2x95x90O)xe2x80x94SH; xe2x80x94C(xe2x95x90W)SH; xe2x80x94C(xe2x95x90O)SR2; xe2x80x94C(xe2x95x90W)SR2; xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90W)NH2; xe2x80x94C(xe2x95x90O)NHR2; xe2x80x94C(xe2x80x94W)NHR2; xe2x80x94C(xe2x95x90O)NR2R3; xe2x80x94C(xe2x95x90W)xe2x80x94NR2R3, xe2x80x94C(xe2x95x90W)NH(CH2)p-(amino acid), a residue of an amino acid or xe2x80x94(CH2)p(amino acid); wherein if R5xe2x80x2 is hydrogen, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl or xe2x80x94NHCOxe2x80x94C1-3alkyl, then at least one of R4xe2x80x2, R6xe2x80x2 and R7xe2x80x2 is not hydrogen or alternatively, wherein at least two of R4xe2x80x2, R5xe2x80x2, R6xe2x80x2, R7xe2x80x2 are not hydrogen.
(c) Z is optionally substituted or unsubstituted acyl, xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90W)xe2x80x94NH2; xe2x80x94C(xe2x95x90O)NHR2; xe2x80x94C(xe2x95x90W)NHR2; xe2x80x94C(xe2x95x90O)NR2R3; xe2x80x94C(xe2x95x90W)NR2R3; xe2x80x94C(xe2x95x90W)NH(CH2)p-(amino acid); a residue of an amino acid, xe2x80x94(CH2)p-(amino acid); xe2x80x94C(xe2x95x90O)R3; xe2x80x94C(xe2x95x90O)H; xe2x80x94C(xe2x95x90W)H; xe2x80x94C(xe2x95x90O)R2; xe2x80x94C(xe2x95x90W)R2; xe2x80x94C(xe2x95x90O)OR3; xe2x80x94C(xe2x95x90O)OH; xe2x80x94C(xe2x95x90W)OH; xe2x80x94C(xe2x95x90O)OR2; xe2x80x94C(xe2x95x90W)xe2x80x94OR2; xe2x80x94C(xe2x95x90O)xe2x80x94SH; xe2x80x94C(xe2x95x90W)SH; xe2x80x94C(xe2x95x90O)SR2; xe2x80x94C(xe2x95x90W)SR2; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and in particular CH3, CF3, vinyl bromide, xe2x80x94CR2R2xe2x80x94S(O)nxe2x80x94R3, xe2x80x94CR2R2NH2, xe2x80x94CR2R2NHR2, xe2x80x94CR2R2NR2, R3 and xe2x80x94CR2R2xe2x80x94C(xe2x95x90O)R2); xe2x80x94CN, or halo (F, Cl, Br or I);
(d) Y is O, S or S(O)n;
(e) each W is independently O, S, xe2x80x94NH2, xe2x80x94NHR2, xe2x80x94NR2R2, xe2x80x94Nxe2x80x94CN, xe2x80x94Nxe2x80x94NH2, xe2x80x94Nxe2x80x94NHR2, xe2x80x94Nxe2x80x94NR2R3, xe2x80x94Nxe2x80x94OH or xe2x80x94Nxe2x80x94OR2;
(f) each R2 is independently hydrogen or an optionally substituted or unsubstituted branched or unbranched lower alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C1-3alkyl, C2-4alkenyl or C2-4alkynyl, and in particular CH3, CF3, vinyl bromide, xe2x80x94CR2R2xe2x80x94S(O)nxe2x80x94R3, xe2x80x94CR2R2NH2, xe2x80x94CR2R2NHR2, xe2x80x94CR2R2NR2R3 and xe2x80x94CR2R2xe2x80x94C(xe2x95x90O)R2);
(g) each R3 is independently hydrogen; optionally substituted or unsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such as an optionally substituted or unsubstituted branched or unbranched C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and in particular CH3, CF3, vinyl bromide, xe2x80x94CR2R2xe2x80x94S(O)nxe2x80x94R3, xe2x80x94CR2R2NH2, xe2x80x94CR2R2NHR2, xe2x80x94CR2R2NR2R3 and xe2x80x94CR2R2xe2x80x94C(xe2x95x90O)R2); optionally substituted or unsubstituted aryl (such as phenyl); optionally substituted or unsubstituted heterocycle; optionally substituted or unsubstituted alkylaryl, optionally substituted or unsubstituted alkylhereterocycle, optionally substituted or unsubstituted aralkyl, optionally substituted or unsubstituted heterocycle-alkyl;
(h) each n is independently 0, 1 or 2; and
(i) each p is independently 0, 1, 2, 3, 4 or 5;
(j) wherein if one or more of the optionally substituted branched or unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower alkenyl or lower alkynyl; acyl; aryl; heterocycle; alkaryl; alkheterocycle; arylalkyl or alkylheterocycle substitutents is substituted, then preferably it is substituted with one or more of halogen (F, Cl, Br or I), xe2x80x94OH, xe2x80x94OR2, xe2x80x94SH, xe2x80x94SR2, oxime (defined herein as xe2x80x94CHxe2x95x90Nxe2x80x94OH), hydrazine (defined herein as xe2x80x94NHxe2x80x94NH2), xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90W)H, xe2x80x94C(xe2x95x90O)R2, xe2x80x94C(xe2x95x90W)R2, xe2x80x94C(xe2x95x90O)OH, xe2x80x94C(xe2x95x90W)OH, xe2x80x94C(xe2x95x90O)OR2, xe2x80x94C(xe2x95x90W)OR2, xe2x80x94C(xe2x95x90O)SH, xe2x80x94C(xe2x95x90W)SH, xe2x80x94C(xe2x95x90O)SR2, xe2x80x94C(xe2x95x90W)SR2, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90W)NH2, xe2x80x94C(xe2x95x90O)xe2x80x94NHR2, xe2x80x94C(xe2x95x90W)NHR2, xe2x80x94C(xe2x95x90O)NR2R3, xe2x80x94C(xe2x95x90W)xe2x80x94NR2R3, xe2x80x94NH2, xe2x80x94NHR2, xe2x80x94NR2R3, xe2x80x94NHSO2xe2x80x94C1-3alkyl, xe2x80x94NW2SO2xe2x80x94C1-3alkyl, xe2x80x94NHCOxe2x80x94C1-3alkyl, xe2x80x94NR2COxe2x80x94C1-3alkyl, xe2x80x94S(O)nxe2x80x94R3, C1-3alkoxy, C1-3thioether, a residue of an amino acid such as xe2x80x94NH(CH2)p-(amino acid) or xe2x80x94C(xe2x95x90W)NH(CH2)p-(amino acid).
In a preferred embodiment, Y is SO2. In another preferred embodiment, Z is an amide function.
In an alternative embodiment, the hydrogen attached to the indole nitrogen can be replaced with lower alkyl, for example, methyl, or aryl, alkaryl or aralkyl.
In another embodiment the invention provides a phenylindole represented generally by formula (I) above, and methods of using such phenylindoles in the treatment of HIV, wherein:
(a) R1 is hydrogen;
(b) R4xe2x80x2, R5xe2x80x2, R6xe2x80x2 and R7xe2x80x2 are independently hydrogen, halogen (F, Cl, Br or I), xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl, xe2x80x94NHCOxe2x80x94C1-3alkyl, oxime, hydrazine, or C1-3 alkyl or alkenyl optionally substituted with one or more of xe2x80x94OH, xe2x80x94SH, xe2x80x94C(O)H, xe2x80x94COOH, halogen (F, Cl, Br or I), xe2x80x94NR2R2, xe2x80x94C1-3 alkoxy or xe2x80x94C1-3 thioether; wherein if R5xe2x80x2 is hydrogen, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl or xe2x80x94NHCOxe2x80x94C1-3alkyl, then at least one of R4xe2x80x2, R6xe2x80x2 and R7xe2x80x2 is not hydrogen;
(c) R2xe2x80x3, R3xe2x80x3, R4xe2x80x3, R5xe2x80x3 and R6xe2x80x3 are independently hydrogen, halogen (F, Cl, Br or I), xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl, xe2x80x94NHCOxe2x80x94C1-3alkyl, xe2x80x94C1-5 alkoxy, oxime, hydrazine, xe2x80x94C1-5 alkyl or alkenyl optionally substituted with one or more of xe2x80x94OH, xe2x80x94SH, xe2x80x94C(O)H, xe2x80x94COOH, halogen (F, Cl, Br or I), xe2x80x94NR2R2, xe2x80x94C1-5 thioether or xe2x80x94C1-5 alkoxy;
(d) Z is xe2x80x94CN, xe2x80x94C(xe2x95x90W)NR2R3, xe2x80x94C(xe2x95x90O)R3, xe2x80x94C(xe2x95x90O)OR3, xe2x80x94CR2R2xe2x80x94S(O)nxe2x80x94R3, xe2x80x94CR2R2NHR2, xe2x80x94CR2R2xe2x80x94COxe2x80x94R3 or substituted or unsubstituted lower alkyl;
(e) Y is O, S, or S(O)n;
(f) each W is independently O, S, xe2x80x94Nxe2x80x94CN or xe2x80x94Nxe2x80x94OR2;
(g) R2 is hydrogen or C1-3 alkyl;
(h) R3 is hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, xe2x80x94C1-5 alkoxy, xe2x80x94OH, xe2x80x94NR2R2, or xe2x80x94(CH2)pC(O)NR2R2,
(i) each n is independently 0, 1 or 2; and
(j) each p is independently 0, 1, 2, 3, 4, or 5.
In still another embodiment the invention provides a phenylindole represented generally by formula (I) above, and methods of using such phenylindoles in the treatment of HIV, wherein:
(a) R1 is hydrogen;
(b) R4xe2x80x2, R5xe2x80x2, R6xe2x80x2, R7xe2x80x2, are independently hydrogen, halogen (F, Cl, Br or I), xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl, xe2x80x94NHCOxe2x80x94C1-3alkyl, oxime (defined herein as xe2x80x94CHxe2x95x90Nxe2x80x94OH), hydrazine (defined herein as xe2x80x94NHxe2x80x94NH2), or C1-3 alkyl or alkenyl optionally substituted with one or more of xe2x80x94OH, xe2x80x94SH, C(O)H, COOH, halogen, NR2R2, C1-3 alkoxy, or C1-3 thioether; wherein if R5xe2x80x2 is hydrogen, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NR2R2, xe2x80x94NHSO2xe2x80x94C1-3alkyl or xe2x80x94NHCOxe2x80x94C1-3alkyl, then at least one of R4xe2x80x2, R6xe2x80x2 and R7xe2x80x2 is not hydrogen;
(c) R2xe2x80x3, R3xe2x80x3, R4xe2x80x3, R5xe2x80x3, and R6xe2x80x3, are independently hydrogen, halogen (F, Cl, Br or I), xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR2, xe2x80x94NHSO2xe2x80x94C1-3alkyl, xe2x80x94NHCOxe2x80x94C1-3alkyl, oxime, hydrazine, xe2x80x94C1-5 alkyl or alkenyl optionally substituted with one or more of xe2x80x94OH, xe2x80x94SH, C(O)H, COOH, halogen, NR2R2, C1-5 thioether, or C1-5 alkoxy, xe2x80x94C1-5 alkoxy, xe2x80x94OH, or xe2x80x94NR2R2,
(d) Z is xe2x80x94C(W)NR2R3, or xe2x80x94COR3,
(e) Y is xe2x80x94S(O)nxe2x80x94 or xe2x80x94Oxe2x80x94, in which n is 0, 1 or 2.
(f) W is O, S, xe2x80x94Nxe2x80x94CN or xe2x80x94Nxe2x80x94OR2;
(g) R2 is hydrogen or C1-3 alkyl,
(h) R3 is s alkyl, C1-5 alkenyl, aryl, or heterocycle, substituted with one or more of C(O)NR2R2, xe2x80x94NR2R2, xe2x80x94(CH2)mC(O)NR1R2, xe2x80x94(CH2)mC(xe2x95x90W)xe2x80x94NH(CH2)p-(amino acid);
(k) each n is independently 0, 1 or 2; and
(l) each p is independently 0, 1, 2, 3, 4, or 5.
In a particular embodiment, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In another particular embodiment, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In yet another particular embodiment, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In yet another particular embodiment, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In another particular embodiment, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In yet another particular embodiment of the present invention, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In yet another particular embodiment of the present invention, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
In yet another particular embodiment of the present invention, the phenylindole is a compound of the structure: 
or a pharmaceutically acceptable salt or prodrug thereof.
The phenylindoles of this invention belong to a class of anti-HIV agents that may inhibit reverse transcriptase activity. These compounds can be assessed for their ability to inhibit reverse transcriptase activity in vitro according to standard screening methods.
In one embodiment the efficacy of the anti-HIV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound""s EC50). In preferred embodiments the compound exhibits an EC50 of less than 15 or preferably, less than 10 micromolar in vitro.
In another embodiment, the active compound exhibits significant activity against drug-resistant forms of HIV, and thus exhibits decreased cross-resistance against currently approved antiviral therapies. The term significant activity against a drug resistant form of HIV means that a compound (or its prodrug or pharmaceutically acceptable salt) is active against the mutant strain with an EC50 against the mutant strain of less than approximately 50, 25, 10 or 1 micromolar concentration. In a preferred embodiment, the non-nucleosides reverse transcriptase inhibitors (NNRTI) displays an EC50 (in molar concentrations) in a mutant HIV strain of less than approximately 5, 2.5, 1 or 0.1 micromolar concentration. In one non limiting embodiment, the HIV mutant strain is a strain with a reverse transcriptase mutation at lysine 103xe2x86x92 asparagine and/or tyrosine 181xe2x86x92 cysteine.
In still another embodiment, the active compound can be administered in combination or alternation with another anti-HIV agent. In combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.